Background: Diabetes is a major health problem in United States of America. Despite extensive study, the exact causes of this disease are not known. However, evidence suggests that all forms of diabetes are associated with reduced beta-cell function and survival. Our laboratory has recently shown that insulin itself controls beta-cell survival. Objective of research: The goal of the proposed research is to characterize the mechanisms through which insulin regulates beta-cell survival in human and mouse islets. We hypothesize that insulin may promote beta-cell survival via a kinase called Raf-1. Description of research project: We will utilize molecular biology, live-cell imaging and knockout mice to dissect the role of Raf-1 in anti-apoptotic beta-cell insulin signaling. Relevancy to diabetes: We expect our proposed experiments to yield new mechanistic information regarding insulin as a beta-cell survival factor. Greater understanding of the control of apoptosis in human islets is crucial to prevent beta-cell death in all types of diabetes and to improve clinical islet transplantation.